The enzymatic conversion of CNS
cholesterol to
24S-hydroxycholesterol, which readily crosses the blood-brain barrier, is the major pathway for brain
cholesterol elimination and brain
cholesterol homeostasis maintenance. The
enzyme mediating this conversion has been characterized at the molecular level (
CYP46) and is mainly located in neurons. Like other
oxysterols,
24S-hydroxycholesterol is efficiently converted into normal
bile acids or excreted in bile in its sulfated and glucuronidated form. Levels of
24S-hydroxycholesterol in the circulation decrease with age in infants and children. In adults, however, the levels appear to be stable. There is accumulating evidence pointing toward a potentially important link between
cholesterol,
beta-amyloid, and
Alzheimer's disease. Concentrations of
24S-hydroxycholesterol in plasma and cerebrospinal fluid (CSF) are significantly higher in
Alzheimer's disease and vascular demented patients at early stages of the disease compared to healthy subjects. Variations in genetic background, time of disease onset, and severity of
dementia are potential sources of variance. Inhibitors of
cholesterol biosynthesis, also termed
statins, seem to have a reductive influence on the generation of the
amyloid precursor
protein, the neuronal secretion of
beta-amyloid, and on de novo
cholesterol synthesis. Recent epidemiological studies indicate that the prevalence of diagnosed AD and
vascular dementia is reduced among people taking
statins for a longer period of time. High-dose
simvastatin treatment (80 mg/day) in patients with
hypercholesterolemia leads to a significant decrease in brain-specific serum
24S-hydroxycholesterol concentrations and indicates a diminished
cholesterol metabolism in the brain. CSF levels of
cholesterol and
lathosterol, a
cholesterol precursor considered to be an
indicator for
cholesterol neogenesis, were significantly decreased in
statin-treated subjects compared to non-treated normo- and hypercholesterolemic subjects. Also, CSF concentrations of
24S-hydroxycholesterol were significantly lower in
statin-treated patients compared to normocholesterolemic subjects. Treatment with high-dose
simvastatin in normocholesterolemic Alzheimer patients for 26 weeks at early stages of the disease results in a significant decrease in Abeta-levels in cerebrospinal fluid. This decrease correlates with the reduction of
24S-hydroxycholesterol.